The compound (xe2x88x92)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8[4R-(3S-hydroxy-1-methyl)piperidinyl]-4H-1-benzopyran-4-one or one of its pharmaceutically acceptable salt forms (known as xe2x80x9cFlavopiridolxe2x80x9d) is an immunomodulator and antiinflammatory agent (U.S. Pat. No. 4,900,727), and inhibitor of oncogene-encoded kinases or growth factor receptor tyrosine kinases (U.S. Pat. No. 5,284,856). Flavopiridol is a strong inhibitor of cyclin dependent kinases (CDKs) including CDK1, CDK2, CDK4, CDK6 and CDK7, (cdk1/clyclin B; cdk2/cyclin A; cdk2/cyclin E; cdk4/cyclin D; cdk6/cyclinD; cdk7/cyclin H) with the potential to cause inhibition of cell cycle progression in G1 and G2 by multiple mechanisms relatable to cdk inhibition. See International Journal of Oncology 9:1143-1168 (1996). Also, Flavopiridol has been shown to inhibit the EGF receptor family, the receptor associated SRC family kinases, and signal transducing kinases. In vitro and in vivo experiments have shown that Flavopiridol is able to inhibit a broad type range of human tumors, leukemias and lymphomas.
(xe2x88x92)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8[4R-(3S-hydroxy-1-methyl)piperidinyl]-4H-1-benzopyran-4-one or a pharmaceutically acceptable salt thereof crystallizes into numerous solvates with solvents such as ethanol, DMSO, methanol, acetonitrile/isopropanol, ethanol/isopropanol, and isopropanol and solvate hydrates such as ethanol/ and isopropanol/water combinations. The preferred form is the Flavopiridol hydrochloride ethanol/water solvate form (hereafter xe2x80x9cForm IIxe2x80x9d).
Although Form II meets pharmaceutical standards, it has a tendency to absorb water if not packaged in water impermeable packaging, which increases cost of production. It is also desirable to have as much stability as possible in the crystalline structure for handling purposes and for approvals through different pharmaceutical regulatory agencies throughout the world.
It is an object of the present invention to provide a form of Flavopiridol as Form I which has superior physical characteristics for use as a pharmaceutical composition.
The present invention comprises pseudopolymorph Form I as defined by x-ray powder diffraction. Preferably, Form I is essentially free of Form II and/or other Flavopiridol forms. It is useful in a pharmaceutical composition comprising an effective amount of Form I and a pharmaceutically acceptable carrier. Form I is useful as a protein kinase inhibitor, cyclin dependent kinase inhibitor, and in the treatment for various forms of cancer.
Form I is further characterized by its ability of being less hygroscopic than Form II e.g., has less weight gain in comparative relative humidities.
Form I is prepared by combining a sufficient quantity of Form II with a sufficient amount of an appropriate azeotropic solvent thus forming an azeotropic mixture; submitting the azeotropic mixture to azeotropic distillation sufficient to form Form I; and optionally recovering Form I therefrom.